Neutrophil to lymphocyte ratio predicts bowel ischemia in non-strangulated adhesive small bowel occlusions: a retrospective analysis from an acute care surgical service.

BACKGROUND: Adhesive small bowel obstruction (ASBO) is a leading cause of hospitalization in emergency surgery. The occurrence of bowel ischemia significantly increases the morbidity and mortality rates associated with this condition. Current clinical, biochemical and radiological parameters have poor predictive value for bowel ischemia. This study is designed to ascertain predictive elements for the progression to bowel ischemia in patients diagnosed with non-strangulated ASBO who are initially managed through conservative therapeutic approaches. METHODS: The study was based on the previously collected medical records of 128 patients admitted to the Department of Acute Care Surgery of Padua General Hospital, from August 2020 to April 2023, with a diagnosis of non-strangulated adhesive small bowel obstruction, who were then operated for failure of conservative treatment. The presence or absence of bowel ischemia was used to distinguish the two populations. Clinical, biochemical and radiological data were used to verify whether there is a correlation with the detection of bowel ischemia. RESULTS: We found that a Neutrophil-Lymphocyte ratio (NLR) > 6.8 (OR 2.9; 95% CI 1.41-6.21), the presence of mesenteric haziness (OR 2.56; 95% CI 1.11-5.88), decreased wall enhancement (OR 4.3; 95% CI 3.34-10.9) and free abdominal fluid (OR 2.64; 95% CI 1.08-6.16) were significantly associated with bowel ischemia at univariate analysis. At the multivariate logistic regression analysis, only NLR > 6.8 (OR 5.9; 95% CI 2.2-18.6) remained independent predictive factor for small bowel ischemia in non-strangulated adhesive small bowel obstruction, with 78% sensitivity and 65% specificity. CONCLUSIONS: NLR is a straightforward and reproducible parameter to predict bowel ischemia in cases of non-strangulated adhesive small bowel obstruction. Employing NLR during reevaluation of patients with this condition, who were initially treated conservatively, can help the acute care surgeons in the early prediction of bowel ischemia onset.

Surgical oncological emergencies in octogenarian patients.

Background: Surgical oncological emergencies represent a frequent challenge in acute settings, with postoperative courses characterized by high morbidity and mortality. An accurate selection of patients who could benefit from surgery is essential to avoid unnecessary invasive treatment. In this study, we tried to determine if advanced age (>80 years) represents a risk factor for negative short-term outcome in patients undergoing emergency surgery for acute abdominal oncological illness. Methods: We retrospectively analyzed the records of patients who underwent emergency oncological surgery at the Department of Acute Care Surgery of Padua General Hospital from January 2018 to December 2022. One hundred two cancer patients were included in the study. Among them, 42 were aged ≥80 years (41%). Multiple preoperative and postoperative parameters were recorded, and the follow-up period was at least 90 days. Multivariate logistic regression analyses were used to identify factors associated with short-term postoperative outcomes. Results: In the octogenarian group, 30-day mortality was 11% vs. 9.5% in the younger group [p = not significant (ns)] and 90-day mortality was 17.6% in the octogenarian group vs. 20.5% in the younger group (p = ns). Postoperative morbidity and hospital length of stay were not significantly different in the two groups. Low albumin levels [odds ratio (OR) 30.6, 9.51-87.07] and elevated lactate dehydrogenase (LDH) levels (OR 26.4, 9.18-75.83) were predictive for short-term mortality in surgical oncological emergencies. Conclusion: Advanced age is not a risk factor for negative outcomes in surgical oncological emergencies. Therefore, surgical options should be considered in octogenarians with oncological emergencies and acceptable clinical conditions. Serum albumin levels and LDH can help predict the postoperative outcome after surgery for oncological emergencies.

FK506 bypasses the effect of erythroferrone in cancer cachexia skeletal muscle atrophy.

Skeletal muscle atrophy is a hallmark of cachexia, a wasting condition typical of chronic pathologies, that still represents an unmet medical need. Bone morphogenetic protein (BMP)-Smad1/5/8 signaling alterations are emerging drivers of muscle catabolism, hence, characterizing these perturbations is pivotal to develop therapeutic approaches. We identified two promoters of "BMP resistance" in cancer cachexia, specifically the BMP scavenger erythroferrone (ERFE) and the intracellular inhibitor FKBP12. ERFE is upregulated in cachectic cancer patients' muscle biopsies and in murine cachexia models, where its expression is driven by STAT3. Moreover, the knock down of Erfe or Fkbp12 reduces muscle wasting in cachectic mice. To bypass the BMP resistance mediated by ERFE and release the brake on the signaling, we targeted FKBP12 with low-dose FK506. FK506 restores BMP-Smad1/5/8 signaling, rescuing myotube atrophy by inducing protein synthesis. In cachectic tumor-bearing mice, FK506 prevents muscle and body weight loss and protects from neuromuscular junction alteration, suggesting therapeutic potential for targeting the ERFE-FKBP12 axis.

Paraneoplastic myopathy-related rhabdomyolysis and pancreatic cancer: A case report and review of the literature.

BACKGROUND: Rhabdomyolysis is a life-threatening condition, often leading to progressive renal failure and death. It is caused by destruction of skeletal muscle and the release of myoglobin and other intracellular contents into the circulation. The most frequent cause of this condition is "crush syndrome", although several others have been described and paraneoplastic inflammatory myopathies associated with various types of cancer are repeatedly reported. CASE SUMMARY: We describe a rare case of a patient with pancreatic cancer who developed rhabdomyolysis early on, possibly due to paraneoplastic myositis leading to acute renal failure and eventually to rapid death. A 78-year-old Caucasian woman was referred to our hospital for obstructive jaundice and weight loss due to a lesion in the pancreatic head. She presented increasingly severe renal insufficiency with anuria, a dramatic increase in creatine phosphokinase (36000 U/L, n.v. 20-180 U/L) and myoglobin (> 120000 µg/L, n.v. 12-70 µg/L). On clinical examination, the patient showed increasing pain in the lower limbs associated with muscle weakness which was severe enough to immobilize her. Paraneoplastic myopathy linked to the malignant lesion of the pancreatic head was suspected. The patient was treated with hemodialysis and intravenous methylprednisolone. Despite all the efforts to prepare the patient for surgery, her general condition rapidly deteriorated and she eventually died 30 d after hospital admission. CONCLUSION: The possible causes of rhabdomyolysis in this patient with pancreatic cancer are discussed, the development of paraneoplastic myopathy being the most likely. Clinicians should bear in mind that these syndromes may become clinically manifest at any stage of the cancer course and their early diagnosis and treatment could improve the patient's prognosis.

A scan of all coding region variants of the human genome, identifies 13q12.2-rs9579139 and 15q24.1-rs2277598 as novel risk loci for pancreatic ductal adenocarcinoma.

Coding sequence variants comprise a small fraction of the germline genetic variability of the human genome. However, they often cause deleterious change in protein function and are therefore associated with pathogenic phenotypes. To identify novel pancreatic ductal adenocarcinoma (PDAC) risk loci, we carried out a complete scan of all common missense and synonymous SNPs and analysed them in a case-control study comprising four different populations, for a total of 14 538 PDAC cases and 190 657 controls. We observed a statistically significant association between 13q12.2-rs9581957-T and PDAC risk (P = 2.46 × 10-9), that is in linkage disequilibrium (LD) with a deleterious missense variant (rs9579139) of the URAD gene. Recent findings suggest that this gene is active in peroxisomes. Considering that peroxisomes have a key role as molecular scavengers, especially in eliminating reactive oxygen species, a malfunctioning URAD protein might expose the cell to a higher load of potentially DNA damaging molecules and therefore increase PDAC risk. The association was observed in individuals of European and Asian ethnicity. We also observed the association of the missense variant 15q24.1-rs2277598-T, that belongs to BBS4 gene, with increased PDAC risk (P = 1.53 × 10-6). rs2277598 is associated with body mass index and is in LD with diabetes susceptibility loci. In conclusion, we identified two missense variants associated with the risk of developing PDAC independently from the ethnicity highlighting the importance of conducting reanalysis of genome-wide association studies (GWASs) in light of functional data.

Extended Distal Pancreatectomy for Cancer of the Body and Tail of the Pancreas: Analysis of Early and Late Results.

Cancer of the body-tail of the pancreas often involves adjacent structures. Thus, surgical treatment may be extended to other organs or vessels in order to achieve radical resection. The aim of this study is to evaluate the safety and efficacy of extended distal pancreatectomy for ductal adenocarcinoma of the body and tail of the pancreas. Between January 2000 and December 2016, 101 patients underwent distal pancreatectomy (DP) for pancreatic cancer: 65 patients underwent standard-DP and 36 extended-DP, including the resection of the partial stomach (n = 12), adrenal gland (n = 7), liver (n = 7), colon (n = 8), celiac axis (n = 6), portal vein (n = 5), jejunum (n = 4) and kidney (n = 4). The two groups were compared in terms of their TNM classification, pathological grade, nodal status, state of resection margins, age, sex and levels of preoperative serum carbohydrate antigen 19-9 (CA 19.9). The morbidity and mortality were not statistically different in the two groups. The two groups disease-free and overall survival rates were significantly influenced by the tumor's stage, nodal status, pathological features and resection margins. Survival was not influenced by the extent of the surgical resection. However, when patients were stratified according to the type of extended resection, survival was worse in the group of patients undergoing vascular resection. Multivariate analysis showed that the stage and resection margins are independent predictors of disease-free and overall survival. Extended distal pancreatectomy may be performed with acceptable morbidity and mortality rates. Survival is not significantly different after standard or extended resection. However, the rate of tumor recurrence is high, and long-term survival is a rare event, especially in those patients who undergo distal pancreatectomy associated with vascular resection.

Exploring the Neandertal legacy of pancreatic ductal adenocarcinoma risk in Eurasians.

BACKGROUND: The genomes of present-day non-Africans are composed of 1-3% of Neandertal-derived DNA as a consequence of admixture events between Neandertals and anatomically modern humans about 50-60 thousand years ago. Neandertal-introgressed single nucleotide polymorphisms (aSNPs) have been associated with modern human disease-related traits, which are risk factors for pancreatic ductal adenocarcinoma (PDAC), such as obesity, type 2 diabetes, and inflammation. In this study, we aimed at investigating the role of aSNPs in PDAC in three Eurasian populations. RESULTS: The high-coverage Vindija Neandertal genome was used to select aSNPs in non-African populations from 1000 Genomes project phase 3 data. Then, the association between aSNPs and PDAC risk was tested independently in Europeans and East Asians, using existing GWAS data on more than 200 000 individuals. We did not find any significant associations between aSNPs and PDAC in samples of European descent, whereas, in East Asians, we observed that the Chr10p12.1-rs117585753-T allele (MAF = 10%) increased the risk to develop PDAC (OR = 1.35, 95%CI 1.19-1.54, P = 3.59 × 10-6), with a P-value close to a threshold that takes into account multiple testing. CONCLUSIONS: Our results show only a minimal contribution of Neandertal SNPs to PDAC risk.

Polymorphic variants involved in methylation regulation: a strategy to discover risk loci for pancreatic ductal adenocarcinoma.

INTRODUCTION: Only a small number of risk factors for pancreatic ductal adenocarcinoma (PDAC) has been established. Several studies identified a role of epigenetics and of deregulation of DNA methylation. DNA methylation is variable across a lifetime and in different tissues; nevertheless, its levels can be regulated by genetic variants like methylation quantitative trait loci (mQTLs), which can be used as a surrogate. MATERIALS AND METHODS: We scanned the whole genome for mQTLs and performed an association study in 14 705 PDAC cases and 246 921 controls. The methylation data were obtained from whole blood and pancreatic cancer tissue through online databases. We used the Pancreatic Cancer Cohort Consortium and the Pancreatic Cancer Case-Control Consortium genome-wide association study (GWAS) data as discovery phase and the Pancreatic Disease Research consortium, the FinnGen project and the Japan Pancreatic Cancer Research consortium GWAS as replication phase. RESULTS: The C allele of 15q26.1-rs12905855 showed an association with a decreased risk of PDAC (OR=0.90, 95% CI 0.87 to 0.94, p=4.93×10-8 in the overall meta-analysis), reaching genome-level statistical significance. 15q26.1-rs12905855 decreases the methylation of a 'C-phosphate-G' (CpG) site located in the promoter region of the RCCD1 antisense (RCCD1-AS1) gene which, when expressed, decreases the expression of the RCC1 domain-containing (RCCD1) gene (part of a histone demethylase complex). Thus, it is possible that the rs12905855 C-allele has a protective role in PDAC development through an increase of RCCD1 gene expression, made possible by the inactivity of RCCD1-AS1. CONCLUSION: We identified a novel PDAC risk locus which modulates cancer risk by controlling gene expression through DNA methylation.

Genetic and non-genetic risk factors for early-onset pancreatic cancer.

BACKGROUND: Early-onset pancreatic cancer (EOPC) represents 5-10% of all pancreatic ductal adenocarcinoma (PDAC) cases, and the etiology of this form is poorly understood. It is not clear if established PDAC risk factors have the same relevance for younger patients. This study aims to identify genetic and non-genetic risk factors specific to EOPC. METHODS: A genome-wide association study was performed, analysing 912 EOPC cases and 10 222 controls, divided into discovery and replication phases. Furthermore, the associations between a polygenic risk score (PRS), smoking, alcohol consumption, type 2 diabetes and PDAC risk were also assessed. RESULTS: Six novel SNPs were associated with EOPC risk in the discovery phase, but not in the replication phase. The PRS, smoking, and diabetes affected EOPC risk. The OR comparing current smokers to never-smokers was 2.92 (95% CI 1.69-5.04, P = 1.44 × 10-4). For diabetes, the corresponding OR was 14.95 (95% CI 3.41-65.50, P = 3.58 × 10-4). CONCLUSION: In conclusion, we did not identify novel genetic variants associated specifically with EOPC, and we found that established PDAC risk variants do not have a strong age-dependent effect. Furthermore, we add to the evidence pointing to the role of smoking and diabetes in EOPC.

Safety and Efficacy of Surgery for Metastatic Tumor to the Pancreas: A Single-Center Experience.

Pancreatic metastases from other neoplasms are rare. The role of surgery for this clinical entity is unclear. The aim of this study was to investigate the role of resection in patients with pancreatic secondary lesions. We observed 44 patients with pancreatic metastases from other tumors. Renal cell carcinoma was the most common primary tumor (n = 19, 43.2%). Thirty-seven patients underwent surgery, and pancreatic resection with curative intent was feasible in 35 cases. Fifteen patients (43.2%) experienced major postoperative complications (Clavien-Dindo > 2), and postoperative mortality rate was 5.4%. The median overall survival and disease-free survival were 38 (range 0-186) and 11 (range 0-186) months, respectively. Overall survival and disease-free survival were significantly longer for pancreatic metastases from renal cell carcinoma when compared to other primary tumors. Multivariate analysis confirmed a pathological diagnosis of metastasis from RCC as an independent prognostic factor for overall survival (OR 2.48; 95% CI, 1.00-6.14; p = 0.05). In conclusion, radical resection of metastases to the pancreas is feasible and safe, and may confer a survival benefit for selected patients. There is a clear benefit of metastasectomy in terms of patient survival for metastases from renal cell carcinoma, while for those with other primary tumors, surgery seems to be mainly palliative.

Identification of Recessively Inherited Genetic Variants Potentially Linked to Pancreatic Cancer Risk.

Although 21 pancreatic cancer susceptibility loci have been identified in individuals of European ancestry through genome-wide association studies (GWASs), much of the heritability of pancreatic cancer risk remains unidentified. A recessive genetic model could be a powerful tool for identifying additional risk variants. To discover recessively inherited pancreatic cancer risk loci, we performed a re-analysis of the largest pancreatic cancer GWAS, the Pancreatic Cancer Cohort Consortium (PanScan) and the Pancreatic Cancer Case-Control Consortium (PanC4), including 8,769 cases and 7,055 controls of European ancestry. Six single nucleotide polymorphisms (SNPs) showed associations with pancreatic cancer risk according to a recessive model of inheritance. We replicated these variants in 3,212 cases and 3,470 controls collected from the PANcreatic Disease ReseArch (PANDoRA) consortium. The results of the meta-analyses confirmed that rs4626538 (7q32.2), rs7008921 (8p23.2) and rs147904962 (17q21.31) showed specific recessive effects (p<10-5) compared with the additive effects (p>10-3), although none of the six SNPs reached the conventional threshold for genome-wide significance (p < 5×10-8). Additional bioinformatic analysis explored the functional annotations of the SNPs and indicated a possible relationship between rs36018702 and expression of the BCL2L11 and BUB1 genes, which are known to be involved in pancreatic biology. Our findings, while not conclusive, indicate the importance of considering non-additive genetic models when performing GWAS analysis. The SNPs associated with pancreatic cancer in this study could be used for further meta-analysis for recessive association of SNPs and pancreatic cancer risk and might be a useful addiction to improve the performance of polygenic risk scores.

Does Pancreatic Fistula Affect Long-Term Survival after Resection for Pancreatic Cancer? A Systematic Review and Meta-Analysis.

BACKGROUND: The impact of postoperative pancreatic fistula (POPF) on survival after resection for pancreatic ductal adenocarcinoma (PDAC) remains unclear. METHODS: The MEDLINE, Scopus, Embase, Web of Science, and Cochrane Library databases were searched for studies reporting on survival in patients with and without POPF. A meta-analysis was performed to investigate the impact of POPF on disease-free survival (DFS) and overall survival (OS). RESULTS: Sixteen retrospective cohort studies concerning a total of 5019 patients with an overall clinically relevant POPF (CR-POPF) rate of 12.63% (n = 634 patients) were considered. Five of eleven studies including DFS data reported higher recurrence rates in patients with POPF, and one study showed a higher recurrence rate in the peritoneal cavity. Six of sixteen studies reported worse OS rates in patients with POPF. Sufficient data for a meta-analysis were available in 11 studies for DFS, and in 16 studies for OS. The meta-analysis identified a shorter DFS in patients with CR-POPF (HR 1.59, p = 0.0025), and a worse OS in patients with POPF, CR-POPF (HR 1.15, p = 0.0043), grade-C POPF (HR 2.21, p = 0.0007), or CR-POPF after neoadjuvant therapy. CONCLUSIONS: CR-POPF after resection for PDAC is significantly associated with worse overall and disease-free survival.

Recent Advances in Pancreatic Neoplasms.

Pancreatic neoplasms, both primary and secondary, include different pathological entities with variable biological behavior and, consequently, different treatment modalities [...].

Genetic Polymorphisms Involved in Mitochondrial Metabolism and Pancreatic Cancer Risk.

BACKGROUND: The mitochondrial metabolism has been associated with pancreatic ductal adenocarcinoma (PDAC) risk. Recent evidence also suggests the involvement of the genetic variability of the mitochondrial function in several traits involved in PDAC etiology. However, a systematic investigation of the genetic variability of mitochondrial genome (mtSNP) and of all the nuclear genes involved in its functioning (n-mtSNPs) has never been reported. METHODS: We conducted a two-phase association study of mtSNPs and n-mtSNPs to assess their effect on PDAC risk. We analyzed 35,297 n-mtSNPs and 101 mtSNPs in up to 55,870 individuals (12,884 PDAC cases and 42,986 controls). In addition, we also conducted a gene-based analysis on 1,588 genes involved in mitochondrial metabolism using Multi-marker Analysis of GenoMic Annotation (MAGMA) software. RESULTS: In the discovery phase, we identified 49 n-mtSNPs and no mtSNPs associated with PDAC risk (P < 0.05). In the second phase, none of the findings were replicated. In the gene-level analysis, we observed that three genes (TERT, SUGCT, and SURF1) involved in the mitochondrial metabolism showed an association below the Bonferroni-corrected threshold of statistical significance (P = 0.05/1588 = 3.1 × 10-5). CONCLUSIONS: Even though the mitochondrial metabolism might be involved in PDAC etiology, our results, obtained in a study with one of the largest sample sizes to date, show that neither n-mtSNPs nor mtSNPs are associated with PDAC risk. IMPACT: This large case-control study does not support a role of the genetic variability of the mitochondrial function in PDAC risk.

Association of Genetic Variants Affecting microRNAs and Pancreatic Cancer Risk.

Genetic factors play an important role in the susceptibility to pancreatic cancer (PC). However, established loci explain a small proportion of genetic heritability for PC; therefore, more progress is needed to find the missing ones. We aimed at identifying single nucleotide polymorphisms (SNPs) affecting PC risk through effects on micro-RNA (miRNA) function. We searched in silico the genome for SNPs in miRNA seed sequences or 3 prime untranslated regions (3'UTRs) of miRNA target genes. Genome-wide association data of PC cases and controls from the Pancreatic Cancer Cohort (PanScan) Consortium and the Pancreatic Cancer Case-Control (PanC4) Consortium were re-analyzed for discovery, and genotyping data from two additional consortia (PanGenEU and PANDoRA) were used for replication, for a total of 14,062 cases and 11,261 controls. None of the SNPs reached genome-wide significance in the meta-analysis, but for three of them the associations were in the same direction in all the study populations and showed lower value of p in the meta-analyses than in the discovery phase. Specifically, rs7985480 was consistently associated with PC risk (OR = 1.12, 95% CI 1.07-1.17, p = 3.03 × 10-6 in the meta-analysis). This SNP is in linkage disequilibrium (LD) with rs2274048, which modulates binding of various miRNAs to the 3'UTR of UCHL3, a gene involved in PC progression. In conclusion, our results expand the knowledge of the genetic PC risk through miRNA-related SNPs and show the usefulness of functional prioritization to identify genetic polymorphisms associated with PC risk.

Perturbed BMP signaling and denervation promote muscle wasting in cancer cachexia.

Most patients with advanced solid cancers exhibit features of cachexia, a debilitating syndrome characterized by progressive loss of skeletal muscle mass and strength. Because the underlying mechanisms of this multifactorial syndrome are incompletely defined, effective therapeutics have yet to be developed. Here, we show that diminished bone morphogenetic protein (BMP) signaling is observed early in the onset of skeletal muscle wasting associated with cancer cachexia in mouse models and in patients with cancer. Cancer-mediated factors including Activin A and IL-6 trigger the expression of the BMP inhibitor Noggin in muscle, which blocks the actions of BMPs on muscle fibers and motor nerves, subsequently causing disruption of the neuromuscular junction (NMJ), denervation, and muscle wasting. Increasing BMP signaling in the muscles of tumor-bearing mice by gene delivery or pharmacological means can prevent muscle wasting and preserve measures of NMJ function. The data identify perturbed BMP signaling and denervation of muscle fibers as important pathogenic mechanisms of muscle wasting associated with tumor growth. Collectively, these findings present interventions that promote BMP-mediated signaling as an attractive strategy to counteract the loss of functional musculature in patients with cancer.

Serum miRNA Profiling for Early PDAC Diagnosis and Prognosis: A Retrospective Study.

BACKGROUND: Tumor stage predicts pancreatic cancer (PDAC) prognosis, but prolonged and short survivals have been described in patients with early-stage tumors. Circulating microRNA (miRNA) are an emerging class of suitable biomarkers for PDAC prognosis. Our aim was to identify whether serum miRNA signatures predict survival of early-stage PDAC. METHODS: Serum RNA from archival 15 stage I-III PDAC patients and 4 controls was used for miRNAs expression profile (Agilent microarrays). PDAC patients with comparable age, gender, diabetes, jaundice and surgery were classified according to survival: less than 14 months (7/15 pts, group A) and more than 22 months (8/15 pts, group B). Bioinformatic data analysis was performed by two-class Significance Analysis of Microarray (SAM) algorithm. Binary logistic regression analyses considering PDAC diagnosis and outcome as dependent variables, and ROC analyses were also performed. RESULTS: 2549 human miRNAs were screened out. At SAM, 76 differentially expressed miRNAs were found among controls and PDAC (FDR = 0.4%), the large majority (50/76, 66%) of them being downregulated in PDAC with respect to controls. Six miRNAs were independently correlated with early PDAC, and among these, hsa-miR-6821-5p was associated with the best ROC curve area in distinguishing controls from early PDAC. Among the 71 miRNAs differentially expressed between groups A and B, the most significant were hsa-miR-3135b expressed in group A only, hsa-miR-6126 and hsa-miR-486-5p expressed in group B only. Eight miRNAs were correlated with the presence of lymph-node metastases; among these, hsa-miR-4669 is of potential interest. hsa-miR-4516, increased in PDAC and found as an independent predictor of survival, has among its putative targets a series of gens involved in key pathways of cancer progression and dissemination, such as Wnt and p53 signalling pathways. CONCLUSIONS: A series of serum miRNAs was identified as potentially useful for the early diagnosis of PDAC, and for establishing a prognosis.

Associations between pancreatic expression quantitative traits and risk of pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma (PDAC) is among the most lethal cancers. Its poor prognosis is predominantly due to the fact that most patients remain asymptomatic until the disease reaches an advanced stage, alongside the lack of early markers and screening strategies. A better understanding of PDAC risk factors is essential for the identification of groups at high risk in the population. Genome-wide association studies (GWAS) have been a powerful tool for detecting genetic variants associated with complex traits, including pancreatic cancer. By exploiting functional and GWAS data, we investigated the associations between polymorphisms affecting gene function in the pancreas (expression quantitative trait loci, eQTLs) and PDAC risk. In a two-phase approach, we analysed 13 713 PDAC cases and 43 784 controls and identified a genome-wide significant association between the A allele of the rs2035875 polymorphism and increased PDAC risk (P = 7.14 × 10-10). This allele is known to be associated with increased expression in the pancreas of the keratin genes KRT8 and KRT18, whose increased levels have been reported to correlate with various tumour cell characteristics. Additionally, the A allele of the rs789744 variant was associated with decreased risk of developing PDAC (P = 3.56 × 10-6). This single nucleotide polymorphism is situated in the SRGAP1 gene and the A allele is associated with higher expression of the gene, which in turn inactivates the cyclin-dependent protein 42 (CDC42) gene expression, thus decreasing the risk of PDAC. In conclusion, we present here a functional-based novel PDAC risk locus and an additional strong candidate supported by significant associations and plausible biological mechanisms.

The Prognostic Value of Low Muscle Mass in Pancreatic Cancer Patients: A Systematic Review and Meta-Analysis.

Low muscle mass is associated with reduced survival in patients with different cancer types. The interest in preoperative sarcopenia and pancreatic cancer has risen in the last decade as muscle mass loss seems to be associated with poorer survival, higher postoperative morbidity, and mortality. The aim of the present study was to review the literature to compare the impact of low muscle mass on the outcomes of patients undergoing surgery for pancreatic adenocarcinoma. An extensive literature review was conducted according to the 2009 Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and 10 articles were analyzed in detail and included in the meta-analysis. Data were retrieved on 2811 patients undergoing surgery for pancreatic cancer. Meta-analysis identified that patients with low muscle mass demonstrated a significantly reduced OS when compared to patients without alterations of the muscle mass (ROM 0.86; 95% CI: 0.81-0.91, p < 0.001), resulting in a 14% loss for the former. Meta-analysis failed to identify an increase in the postoperative complications and length of stay of patients with low muscle mass. Our analysis confirms the role of low muscle mass in influencing oncologic outcomes in pancreatic cancer. Its role on surgical outcomes remains to be established.